Coronaviruses cause disease of the respiratory, enteric and central nervous systems. Until recently, these viruses were thought to cause mild symptoms, such as the common cold. This perception changed after the severe acute respiratory syndrome (SARS) outbreak in 2003, caused by the SARS-Coronavirus (SARS-CoV). The virus spread rapidly around the world causing over 8000 infections in 32 countries leading to over 800 deaths. In 2012, another highly pathogenic human coronavirus emerged from the Middle East called the Middle East respiratory syndrome-Coronoavirus (MERS- CoV). This virus currently has infected over 800 people, resulting in over 300 deaths in 21 countries. These outbreaks demonstrate that Coronaviruses are a major threat to public health, and to date, there are no effective therapies to target either SARS-CoV or MERS-CoV. The broad objective of this study is to identify FDA-approved drugs that may be repurposed to treat infections caused by Coronaviruses, as well as to determine their cellular and molecular mechanisms of action in preventing disease. Abl kinase inhibitors inhibit infection by both SARS-CoV and MERS-CoV. Preliminary data demonstrates that Abl kinase inhibitors block replication at early steps in the virus life cycle. Aim 1 of the study will determine whether and how Abl kinase inhibitors prevent Coronavirus trafficking through the endosome/lysosome pathway and whether key endosomal fusion proteins, like Cathepsin L, are affected by ABL kinase inhibitors. Aim 2 will identify whether Abl kinase inhibitors prevent Coronavirus replication and lung pathology in mice. The in vivo inhibition studies will utilize both an established lethal SARS-CoV mouse model and a newly developed MERS-CoV mouse model using a novel human DPP4 transgenic mice. Given that two distinct Coronaviruses have emerged in the last decade, it is imperative to find effective treatments for SARS-CoV and MERS-CoV infection. These tools will allow healthcare providers to access treatments and prevent future disease outbreaks.